Systems and related methods for optimization of multi-electrode nerve pacing

ABSTRACT

This disclosure describes, among other embodiments, systems and related methods for selecting electrode combinations to be used during nerve pacing procedures. A first set of electrode combinations of a nerve pacing system, such as a phrenic nerve pacing system for diaphragm activation, may be mapped (or tested) to determine the location of the electrode combinations relative to a target nerve. Once the general location of the target nerve is known, a more localized second set of electrode combinations may be tested to determine the most suitable electrode combinations for nerve stimulation. At various stages of the mapping process, electrode combinations that are non-optimal may be discarded as candidates for use in a nerve pacing procedure. The systems and methods described herein may allow for the selection of electrode combinations that are most suitable for stimulation of the left and right phrenic nerves during diaphragm pacing.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/095,773, filed Apr. 11, 2016, which is a continuation of U.S.application Ser. No. 14/600,763, filed Jan. 20, 2015 (now U.S. Pat. No.9,333,363, issued on May 10, 2016), which claims priority under 35U.S.C. § 119(e) to U.S. Provisional Application No. 61/929,901, filedJan. 21, 2014. Each of the above-referenced applications is herebyincorporated by reference herein in its entirety.

TECHNICAL FIELD

This disclosure relates to restoration, enhancement, and/or modulationof diminished neurophysiological functions using electrical stimulation.Some embodiments provide methods for mapping and selecting the optimalelectrodes that are in close anatomical proximity to a target nerve.Non-limiting embodiments include nerve stimulation apparatus, electrodestructures, electrodes, sensors, and related methods.

BACKGROUND

Electrical stimulation of nerves is widely applied in the treatment of arange of conditions and may be applied to control muscle activity or togenerate sensations. Nerves may be stimulated by surgically implantingelectrodes in, around or near the nerves and activating the electrodesby means of an implanted or external source of electricity.

The phrenic nerves normally transmit signals from the brain that causethe contractions of the diaphragm necessary for breathing. However,various conditions can prevent appropriate signals from being deliveredto the phrenic nerves. These include:

-   -   permanent or temporary injury or disease affecting the spinal        cord or brain stem;    -   Amyotrophic Lateral Sclerosis (ALS);    -   decreased day or night ventilatory drive (e.g. central sleep        apnea, Ondine's curse); and    -   decreased ventilatory drive while under the influence of        anesthetic agents and/or mechanical ventilation.        These conditions affect a significant number of people.

Intubation and positive pressure mechanical ventilation (MV) may be usedfor periods of several hours or several days, sometimes weeks, to helpcritically ill patients breathe while in intensive care units (ICU).Some patients may be unable to regain voluntary breathing and thusrequire prolonged or permanent mechanical ventilation. Althoughmechanical ventilation can be initially lifesaving, it has a range ofsignificant problems and/or side effects. Mechanical ventilation:

-   -   often causes ventilator-induced lung injury (VILI) and alveolar        damage which can lead to accumulation of fluid in the lungs and        increased susceptibility to infection (ventilator-associated        pneumonia; VAP);    -   commonly requires sedation to reduce discomfort and anxiety in        acutely intubated patients;    -   causes rapid atrophy of the disused diaphragm muscle        (ventilator-induced diaphragm dysfunction, VIDD);    -   can adversely affect venous return because the lungs are        pressurized and the diaphragm is inactive;    -   interferes with eating and speaking;    -   requires apparatus that is not readily portable; and    -   increases the risk of dying in a hospital if the patient fails        to regain normal breathing and becomes ventilator-dependent.

A patient who is sedated and connected to a mechanical ventilator cannotbreathe normally because the central neural drive to the diaphragm andaccessory respiratory muscles is suppressed. Inactivity leads to muscledisuse atrophy and an overall decline in well-being. Diaphragm muscleatrophy occurs rapidly and can be a serious problem to the patient.According to a published study of organ donor patients (Levine et al.,New England Journal of Medicine, 358: 1327-1335, 2008), after only 18 to69 hours of mechanical ventilation, all diaphragm muscle fibers hadshrunk on average by 52-57%. Muscle fiber atrophy results in muscleweakness and increased fatigability. Therefore, ventilator-induceddiaphragm atrophy could cause a patient to become ventilator-dependent.It has been reported that over 840,000 ICU patients in the UnitedStates, Europe and Canada become ventilator dependent every year.

It is well known that for certain patients who have permanentrespiratory insufficiency due to absent or reduced central drivedescending from the brain stem, it is feasible and advantageous torhythmically activate the diaphragm muscle by electrically stimulating(“pacing”) the phrenic nerves using implanted electrodes. Severalmethods have been disclosed.

Method 1 uses cuff-like electrodes surgically implanted in the neck orupper chest to directly stimulate the phrenic nerves, such as the MarkIV Breathing Pacemaker System available from Avery Biomedical Devices,Inc. of Commack, N.Y., USA. The electrodes are connected to surgicallyimplanted receivers and mated to external transmitters by antennas wornover the implanted receivers. Implanting electrodes for phrenic nervepacing requires significant surgery that can be risky and complicated bythe fact that phrenic nerves are thin (approximately 2 mm in diameter),delicate, and located amidst major blood vessels deep in the chest. Thistype of surgery involves significant cost and is typically onlyindicated for certain patients who would otherwise depend on mechanicalventilation for the rest of their lives.

Method 2 uses implanted intramuscular electrodes to pace the diaphragm,such as the NeuRx Diaphragm Pacing System® marketed by SynapseBiomedical Inc. of Oberlin, Ohio. Surgical anesthesia and laparoscopicsurgery are required to map the motor points in the diaphragm muscle andsuture several electrodes near the motor points. This type of surgeryalso involves significant time and cost and is currently only indicatedfor spinal cord injury (SCI) or amyotrophic lateral sclerosis (ALS)patients, who would otherwise depend on mechanical ventilation for therest of their lives.

In some patients who were paced with either Method 1 or Method 2, it wasfound that the rhythmic negative-pressure breathing action provided byphrenic nerve pacing contributed to reducing the rate and extent of lunginjury and infections, compared to mechanically ventilated patients.Phrenic pacing was also shown by Ayas et al. (1999; “Prevention of humandiaphragm atrophy with short periods of electrical stimulation”) to bean effective method for preserving or increasing the strength and theendurance of the diaphragm muscle paralyzed by a SCI. This type ofevidence relates to a well-known fundamental physiological effect ofelectrical activation of muscle nerves, upon which the currentdisclosure is, in part, based on.

Method 3 relates to a system and method using intravascularly implantedelectrodes to stimulate a nerve, developed by Joaquin Andres Hoffer anddescribed in U.S. Pat. No. 8,571,662 entitled “Transvascular NerveStimulation Apparatus and Methods,” which is hereby incorporated byreference in its entirety. Critically ill ICU patients are not typicallyeligible for Methods 1 and 2. For short-term use in ICU patients, Method3 has unique advantages due to the fact that it does not requireinvasive surgery that would typically be performed under fullanaesthesia. Method 3 rhythmically activates the diaphragm through atemporary, removable, multi-lumen, multi-electrode catheter that ispercutaneously inserted into central veins (e.g., left subclavian vein,superior vena cava) of a patient. In critically ill patients who wouldtypically fail to wean and become ventilator-dependent, the pacingtherapy described in U.S. Pat. No. 8,571,662 is expected to prevent,mitigate, or reverse diaphragm muscle-disuse atrophy and maintaindiaphragmatic endurance, thus facilitating successful weaning ofpatients from mechanical ventilation.

SUMMARY

Short-term pacing of the diaphragm muscle in ICU patients who aretemporarily dependent on mechanical ventilation can be reasonablyexpected to prevent, slow down, or reverse the rapid progression of thetypical MV-induced diaphragm muscle disuse atrophy. When the catheter issuitably placed inside the central veins as described above inconnection with Method 3, it is important to select the optimum bipolarelectrode combinations, which may be pairs of bipolar electrodes, fornerve stimulation. One factor for determining whether an electrodecombination is optimum may be proximity to the target nerve. Inselecting the optimum electrode combination, lower and safer electricalcharge and currents can be used to activate the phrenic nerves, thuspreventing overstimulation or unwanted activation of nearby structuressuch as other nerves, muscles, or the heart.

One embodiment of the present disclosure provides an automated algorithmand method to map and select optimum electrode pairs depending on pacingparameters, sensing parameters, and/or a multitude of other parameters.The algorithm and the method to map and select the optimum electrodesdescribed in this disclosure may be useful for trans-vascular phrenicnerve pacing therapy. In addition, the paced diaphragm may restorenegative pressure ventilation, thereby providing a more physiologicalrespiratory pattern and reducing the levels of positive pressureventilation and its harmful effects on the lungs.

Other embodiments of the disclosure include: an algorithm to generate amap of pacing parameters, sensing parameters and/or a multitude of otherparameters for individual electrodes on a multi-electrode catheter, analgorithm for mapping the target nerve relative to the location of anelectrode structure within a blood vessel, an algorithm for theautomatic selection of optimum electrodes, and an algorithm to monitorthe efficacy of the stimulation during delivery of therapy via theselected electrodes. Such algorithms may be applied in methods orembodied in apparatus. While these and other embodiments may be appliedtogether, individual embodiments may be applied in other combinationsand contexts. For example, algorithms described herein may be applied incombination with various neurovascular pacing or sensing systems knownin the art for various diagnostic and/or therapeutic applications.

Embodiments of the disclosure may be applied for restoring breathing,treating conditions such as disuse muscle atrophy and chronic pain, andother uses involving nerve stimulation. Embodiments of the disclosuremay be applied in the treatment of acute or chronic conditions.Embodiments of the disclosure also may be applied to evaluate the needto reposition or remove and replace electrode structures in a patient.

One embodiment of the disclosure relates to transvascular stimulation ofnerves. In transvascular stimulation, suitable arrangements of one ormore electrodes are positioned in a blood vessel that is anatomicallyclose to a nerve to be stimulated. Electrical currents pass from theelectrodes through a wall of the blood vessel to stimulate the targetnerve.

Another embodiment of the disclosure relates to transvascularstimulation of nerves in the neck and chest of a human or other mammal(e.g., a pig, a chimpanzee). FIGS. 1 and 15 illustrate the anatomy ofselected nerves and blood vessels in the neck and chest of a human and,in particular, the relative locations of the left and right phrenicnerves (PhN), vagus nerves (VN), internal jugular veins (UV),brachiocephalic veins (BCV), superior vena cava (SVC) and subclavianveins (ScV).

In one exemplary embodiment, a method of electrical stimulation mayinclude: delivering a series of first electrical stimulations to a nervevia each of a first plurality of electrode combinations one at a time;monitoring a first patient response to each of the first electricalstimulations of the nerve; selecting a first subset of the firstplurality of electrode combinations based on the first patient responsesindicating that the first subset is in proximity to the nerve; based onelectrodes within the first subset of the first electrode combinations,determining a second plurality of electrode combinations; delivering aseries of second electrical stimulations to the nerve via each of thesecond plurality of electrode combinations one at a time; monitoring asecond patient response to each of the second electrical stimulations ofthe nerve; and based on the second patient responses, selecting a secondsubset of the second plurality of electrode combinations, wherein thesecond subset includes electrode combinations having greater secondpatient responses than other of the second plurality of electrodecombinations.

The method of electrical stimulation may additionally or alternativelyinclude one or more of the following steps or features: the firstelectrical stimulations may include a plurality of electrical pulsesdelivered during end-expiration phases of one or more patient breaths;each of the plurality of electrical pulses may have a different chargethan other of the plurality of electrical pulses; each of the pluralityof electrical pulses may have the same charge as other of the pluralityof electrical pulses; the second electrical stimulations may bedelivered after the first electrical stimulations; each of the steps ofmonitoring a first patient response and monitoring a second patientresponse may include obtaining information from a sensor indicative ofat least one of air flow, volume, or pressure; at least one of the stepsof monitoring a first patient response and monitoring a second patientresponse may include obtaining information from a sensor indicative ofat least one of electromyographic activity, central venous pressure,heart rate, chest wall acceleration, blood oxygen saturation, carbondioxide concentration, catheter location, mechanical movement, orresistance; the first subset of the first plurality of electrodecombinations may be located along a portion of a catheter; the electrodecombinations of the first and second plurality of electrode combinationsmay include bipolar electrode pairs; selecting the first subset of thefirst plurality of electrode combinations may include ranking theelectrode combinations of the first plurality of electrode combinationswith respect to the first patient responses, and selecting the secondsubset of the second plurality of electrode combinations may includeranking the electrode combinations of the second plurality of electrodecombinations with respect to the second patient responses, and the firstand second patient responses may be indicative of diaphragm responses tothe respective first and second electrical stimulations; at least one ofthe steps of selecting the first subset of the first plurality ofelectrode combinations or selecting the second subset of the secondplurality of electrode combinations may include ranking electrodecombinations with respect to activation threshold and discardingelectrode combinations having activation thresholds higher thanactivation thresholds of other electrode combinations; at least one ofthe first or second patient responses may include an undesirable effecton a physiological feature other than the diaphragm, and selection ofthe respective first or second subset of the first or second pluralityof electrode combinations does not include an electrode combinationcausing the undesirable effect; the method may further comprisedetermining a recruitment curve corresponding to at least one electrodecombination of the second subset of the second plurality of electrodecombinations; the method may further comprise adjusting a pulse widthand an amplitude of the current to one of the electrode combinations ofthe first or second plurality of electrode combinations, such that thefirst or second electrical stimulations cause graded nerve recruitmentwithin a preset pulse width range; the electrodes within the firstplurality of electrode combinations may be located on an elongated body;the electrodes within the first plurality of electrode combinations maybe proximal electrodes located on a proximal portion of the elongatedbody, the nerve may be a left phrenic nerve, and the elongated body mayfurther include distal electrodes located on a distal portion of theelongated body, and the method may further include: delivering a seriesof third electrical stimulations to a right phrenic nerve via each of athird plurality of electrode combinations one at a time, wherein thethird plurality of electrode combinations includes the distalelectrodes; monitoring a third patient response to each of the thirdelectrical stimulations of the nerve; selecting a third subset of thethird plurality of electrode combinations based on the third patientresponses indicating that the third subset is in proximity to the rightphrenic nerve; based on electrodes within the third subset of the thirdelectrode combinations, determining a fourth plurality of electrodecombinations; delivering a series of fourth electrical stimulations tothe right phrenic nerve via each of the fourth plurality of electrodecombinations one at a time; monitoring a fourth patient response to eachof the fourth electrical stimulations of the nerve; and based on thefourth patient responses, selecting a fourth subset of the fourthplurality of electrode combinations, wherein the fourth subset includeselectrode combinations having greater fourth patient responses thanother of the fourth plurality of electrode combinations; the method mayfurther include positioning the proximal portion of the elongated bodyin a first blood vessel proximate a left phrenic nerve and positioningthe distal portion of the elongated body in a second blood vesselproximate a right phrenic nerve; and a rate of the first electricalstimulations and a rate of the second electrical stimulations may bebased at least in part on: a) a duration of a correspondingend-expiratory phase, and b) a duration of the corresponding first andsecond patient responses.

In another exemplary embodiment, a method of electrical stimulation mayinclude: delivering a first electrical stimulation to a nerve using afirst electrode combination, wherein the first electrical stimulationincludes a first plurality of electrical pulses delivered during anend-expiration phase of each of one or more first patient breaths;delivering a second electrical stimulation to the nerve using a secondelectrode combination, wherein the second electrical stimulationincludes a second plurality of electrical pulses delivered during anend-expiration phase of each of one or more second patient breathsdifferent than the first patient breaths; monitoring a response of adiaphragm to each of the first and second electrical stimulations; andbased on the diaphragm responses, determining a nerve activationthreshold corresponding to each of the first and second electrodecombinations.

The method of electrical stimulation may additionally or alternativelyinclude one or more of the following steps or features: the first andsecond electrode combinations may be located in a blood vessel of apatient receiving breathing assistance from a ventilator; the nerve maybe a phrenic nerve; the first and second electrode combinations mayinclude bipolar electrode pairs; monitoring the response of thediaphragm may include sensing with a sensor at least one of flow,volume, or pressure; the nerve activation threshold may be a thresholdcharge value between a first charge value that will not cause nerverecruitment and a second charge value that will always cause nerverecruitment; approximately half of a plurality of electrical pulses,each delivering a nominal threshold charge value, may cause nerverecruitment.

In one embodiment, a diaphragm pacing system may include: an electrodeassembly including a plurality of electrodes; at least one sensorconfigured to monitor a patient response to electrical stimulation; anda stimulation control unit configured to: deliver a series of firstelectrical stimulations to a nerve via each of a first plurality ofelectrode combinations one at a time; receive input from the at leastone sensor indicative of first patient responses to the series of firstelectrical stimulations; select a first subset of the first plurality ofelectrode combinations based on the first patient responses indicatingthat the first subset is in proximity to the nerve; based on electrodeswithin the first subset of the first electrode combinations, determine asecond plurality of electrode combinations; deliver a series of secondelectrical stimulations to the nerve via each of the second plurality ofelectrode combinations one at a time; receive input from the at leastone sensor indicative of second patient responses to the series ofsecond electrical stimulations; and based on the second patientresponses, select a second subset of the second plurality of electrodecombinations, wherein the second subset includes electrode combinationshaving greater second patient responses than other of the secondplurality of electrode combinations.

The system may additionally or alternatively include one or more of thefollowing features: the electrode assembly may be a catheter configuredfor insertion into a venous system of a patient; the patient responsemay be at least one of air flow, volume, or pressure; the patientresponse may be at least one of electromyographic activity, centralvenous pressure, heart rate, chest wall acceleration, blood oxygensaturation, carbon dioxide concentration, catheter location, mechanicalmovement, or resistance; each of the first and second electricalstimulations may include a plurality of electrical pulses, and thestimulation control unit may be further configured to deliver thepluralities of electrical pulses during end-expiratory phases of apatient receiving breathing assistance from a ventilator; the patientresponses may be indicative of a diaphragm response to electricalstimulation; the stimulation control unit may be configured to selectthe second subset such that the second subset includes electrodecombinations having lower activation thresholds than other of the secondplurality of electrode combinations; the stimulation control unit may beconfigured to halt delivery of electrical stimulations to an electrodecombination of the first or second plurality of electrode combinationsbased on a determination that an activation threshold corresponding tothe electrode combination is higher than an activation thresholdcorresponding to another electrode combination of the first or secondplurality of electrode combinations; the stimulation control unit mayconfigured to adjust a pulse width and an amplitude of the current ofone of the first or second electrical stimulations; the stimulationcontrol unit may be configured to adjust an amplitude of the current ofone of the first or second electrical stimulations if the patientresponse to the one of the first or second electrical stimulationsindicates supramaximal recruitment of a nerve; and the at least onesensor may include two or more sensors.

Further embodiments of the disclosure and features of exampleembodiments are illustrated in the appended drawings and/or described inthe text of this specification and/or described in the accompanyingclaims. It may be understood that both the foregoing general descriptionand the following detailed description are exemplary and explanatoryonly and are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram showing the locations of the left andright phrenic nerves in a patient in relation to the heart and diaphragmof the patient and the placement of a multi-electrode catheter,according to an exemplary embodiment.

FIG. 2 is a block diagram of the components of one embodiment of adiaphragm pacing system.

FIG. 3 is one example of multi-electrode catheter that can be used fortrans-vascular phrenic nerve stimulation to be positioned within theleft subclavian vein and superior vena cava of the patient, according toan exemplary embodiment.

FIG. 4A is one example of two pairs of catheter-mounted phrenic nervestimulating electrodes positioned within the left subclavian vein of thepatient in close proximity to the left phrenic nerve, according to anexemplary embodiment.

FIG. 4B is one example of two pairs of catheter-mounted phrenic nervestimulating electrodes positioned within the superior vena cava of thepatient in close proximity to the right phrenic nerve, according to anexemplary embodiment.

FIG. 5 shows a theoretical electrical recruitment curve for a targetnerve, according to an exemplary embodiment.

FIG. 6 shows airway pressure and airway flow curves and illustrates theinspiration, expiration, and end-expiration phases during mechanicalventilation, according to an exemplary embodiment.

FIG. 7 shows different stimulation modes that can be used forstimulating phrenic nerves, according to an exemplary embodiment.

FIG. 8 shows different stimulation modes that can be used in synchronywith mechanical ventilation, with stimulation delivered during theend-expiration phases.

FIG. 9A illustrates characteristics of diaphragm pacing in synchronywith mechanical ventilation, according to an exemplary embodiment. Theplot shows flow signals, stimulation charge, diaphragm response, pulsewidth modulation, and current. It also shows an exemplary preconfiguredPulse Width Zone indicating the range of pulse width values within whichthreshold activation is desired.

FIG. 9B illustrates diaphragm pacing in synchrony with mechanicalventilation and shows flow, pressure, EMG, and acceleration measurementscorresponding to electrical stimulation of a phrenic nerve, according toan exemplary embodiment.

FIG. 10A is an example of recruitment curve acquired by best-fitting ofa set of individual data points, according to an exemplary embodiment.

FIG. 10B is an example of recruitment curve acquired by averagingmultiple data points obtained using each pulse width value, according toan exemplary embodiment.

FIG. 11 is an example of preconfigured electrode pairs used in a firststage of an algorithm to identify a localized area of the catheter thatis likely located anatomically closest to a target nerve, according toan exemplary embodiment.

FIG. 12 is an example of a second stage of the algorithm during whichall the electrodes within the identified catheter zone in stage one areevaluated, according to an exemplary embodiment. One goal may be toidentify the optimal electrode combinations.

FIG. 13 shows a flowchart of a mapping algorithm, according to anexemplary embodiment.

FIG. 14A shows a flowchart of a first stage of the mapping algorithm ofFIG. 13, according to an exemplary embodiment.

FIG. 14B shows a flowchart of a second stage of the mapping algorithm ofFIG. 13, according to an exemplary embodiment.

FIG. 14C shows a flowchart of a third stage of the mapping algorithm ofFIG. 13, according to an exemplary embodiment.

FIG. 15 shows a flowchart of a supervisory algorithm, according to anexemplary embodiment.

DETAILED DESCRIPTION General Overview

This disclosure describes, among other embodiments, systems and relatedmethods for selecting electrode combinations to be used during nervepacing procedures. Multiple electrode combinations of an electrodeassembly of a nerve pacing system, such as a diaphragm pacing system,may be mapped (or tested) to determine each combination's relativeefficacy when electrically stimulating a target nerve. Stimulationefficacy in this context may refer to, for example, the ability toconsistently stimulate a nerve with lowest possible charge perstimulation pulse. Typically, the charge required to elicit stimulationdepends on the electrode location relative to a target nerve—the shorterthe distance between the electrode combination and target, the lower therequired charge per pulse. At various stages of the mapping process,electrode combinations that require higher charges to stimulate a nerve,that do not maximally stimulate the nerve fast enough when modulatingcharge, that maximally stimulate the nerve too soon when modulatingcharge, that do not stimulate the nerve in a stable and predictablemanner, that cause undesired stimulation of other nerves or anatomy, orthat otherwise are non-optimal may be discarded as candidates for use ina nerve pacing procedure. In one embodiment, the mapping process may becarried out prior to diaphragm pacing via electrical stimulation of thephrenic nerves, and the selected electrode combination or combinationsmay be used to stimulate the phrenic nerves during subsequent diaphragmpacing. In some embodiments, the mapping process may be carried outafter the start of diaphragm pacing to ensure that the optimal electrodecombinations are being used to stimulate the phrenic nerves. In otherembodiments, the mapping process may be carried out both prior todiaphragm pacing and at one or more times during pacing to ensure thatthe optimal electrodes are used during the entire stimulation period.

The components of an example diaphragm pacing system will now bedescribed in detail. As shown in FIG. 1, the system may include amulti-electrode assembly 2. The assembly 2 may include an elongated body4, in this example a catheter, where electrodes 6 are placedlongitudinally along the length of the elongated body 4. The cathetermay be percutaneously inserted rapidly using the Seldinger techniquewith assistance from ultrasound imaging or any other suitable insertionmethod. A guide wire may be first inserted through a hypodermic needleinto the vein, and the distal tip of the catheter may then be passedover the guide wire and advanced into the vein. The shape and mechanicalproperties of the catheter may be designed to urge the catheter togently hug the vein wall in regions adjacent to the right and leftphrenic nerves.

FIG. 3 illustrates one embodiment of a multi-electrode assembly 2. FIG.3 shows two views of assembly 2 rotated 90 degrees relative to eachother about the axis of elongated body 4. The elongated body 4 may be acatheter having a plurality of distal electrodes 6 a-6 f and a pluralityof proximal electrodes 6 g-6 r. Although six distal electrodes andtwelve proximal electrodes are shown, the elongated body 4 may includeany number of electrodes. The electrodes may be held on a plurality ofelectrode assemblies within the catheter. In one embodiment, theelectrodes may be exposed to the exterior of the elongated body 4through apertures. The apertures may confine electrical fields createdby electrode combinations to specific desired areas. The elongated body4 may be configured such that the left electrode array (electrodes 6 g-6r) is configured to stimulate a patient's left phrenic nerve and theright electrode array (6 a-6 f) is configured to stimulate a patient'sright phrenic nerve.

While two electrodes may be used for bipolar stimulation of each of theleft and right phrenic nerves, it will be appreciated that other numbersof electrodes may be practiced with embodiments of the presentdisclosure and may form an electrode combination. For example, fourelectrodes can be used for stimulating each phrenic nerve, as shown inFIGS. 4A and 4B. In some embodiments, a single electrode may be used forso-called monopolar stimulation of nerves, in which case the stimulationcircuit is completed by using a reference electrode placed at anotherlocation in or on the body. An electrode combination may be any set ofone or more electrodes configured to electrically stimulate a nerve.Charge-balanced biphasic stimulation pulses may minimize tissue damageand electrode corrosion.

FIG. 4A and FIG. 4B illustrate one embodiment of an elongated body 4,which may be a catheter or other structure to support electrodes,showing two channels of transvascular stimulation delivered to the leftphrenic nerve PhN (Left) by endovascular electrodes placed in the leftsubclavian vein and two channels of transvascular stimulation deliveredto the right phrenic nerve PhN (Right) by endovascular electrodes placedalong the lateral wall of the superior vena cava SVC. Each phrenic nervecan be partially or fully recruited from more than one endovascularelectrode combination.

Partial nerve recruitment from more than one electrode combination maybe useful to reduce muscle fatigue over time. The diaphragm pacingsystem may alternate back and forth between electrode combinations(e.g., between the left pair and the right pair in FIG. 4A; or betweenthe left pair and the right pair in FIG. 4B) used for nerve stimulationbased on a certain time interval or a certain number of breaths. Inanother embodiment that may reduce muscle fatigue, a nerve may berecruited using two electrode combinations that are stimulated out ofphase, thus allowing stimulation of each channel at a lower rate withoutcausing increased ripple in the resulting muscle force. Use of multipleelectrode combinations may also allow for consistent recruitment of anerve if the elongated body 4 moves within the patient.

For more information regarding the endovascular placement of a pluralityof electrodes as well as the configuration of electrode structures thatcan be practiced with embodiments of the present disclosure, see U.S.application Ser. No. 12/524,571, filed Jul. 25, 2009, now U.S. Pat. No.8,571,662, U.S. Provisional Application No. 61/907,993, filed Nov. 22,2013, titled “Apparatus for Assisted Breathing by Transvascular NerveStimulation and Related Methods,” and U.S. application Ser. No.14/550,485, filed Nov. 21, 2014, titled “Apparatus and Methods forAssisted Breathing by Transvascular Nerve Stimulation,” the disclosuresof each of which are hereby expressly incorporated by reference hereinfor all purposes in their entirety. Additionally, while electrodesreceiving charge-balanced biphasic stimulus pulses may be utilized toemit the stimulation pulses into the phrenic nerves, otherconfigurations are possible. For example, several cathodal electrodecontacts may be used in conjunction with a single anodal electrodecontact, or vice versa.

Referring to FIG. 2, a diaphragm pacing system may include electrodes 6in electrical communication with a stimulation control unit 8. Eachelectrode may be electrically connected to the stimulation control unit8 via lead(s). The system may further include one or more sensors 12configured to monitor the response to stimulation and/or otherphysiological characteristics of the patient. One or more sensors 12 canbe part of a feedback control scheme for regulating the stimulationadministered to the patient.

The one or more sensors 12 can transmit data to the stimulation controlunit 8 indicative of one or more of the following: electromyographicactivity (intramuscular, surface, and/or intraesophageally monitored),central venous pressure (any specific component of this signal), heartrate, chest wall acceleration, blood oxygen saturation, carbon dioxideconcentration, catheter position/depth within vein, mechanical movement(e.g., from accelerometers, length gauges, and/or strain gauges)resistance (e.g., from impedance pneumographs, and/or piezoresistivesensors) and/or other physiological or mechanical parameters. It will beappreciated that the information can be appropriately processed (e.g.,filtered, conditioned, amplified, etc.) prior to use by the stimulationcontrol unit 8.

The term “volume” as used herein includes, but is not limited to,Inspired Tidal Volume, Expired Tidal Volume, or Minute Volume. The term“pressure” as used herein includes, but is not limited to, AirwayPressure, Alveolar Pressure, Ventilator Pressure, Esophageal Pressure,Gastric Pressure, Transdiaphragmatic Pressure, Intra-Thoracic Pressure,Positive End-Expiratory Pressure, or Pleural Pressure. Any pressure maybe expressed via its Peak Pressure, Mean Pressure, Baseline Pressure, orPressure-Time Product associated with a phase of a ventilator breath.The term “flow” as used herein includes, but is not limited to,Inspiratory Air Flow or Expiratory Air Flow.

The multi-electrode assembly 2 can also optionally monitor physiologicalvariables of the subject by virtue of its placement in the centralveins. Such monitored physiological variables can include, but are notlimited to: central venous pressure, electrocardiogram, and mixed venousoxygen saturation.

The diaphragm pacing system can additionally or alternatively include abreath sensor 14 (FIG. 2) for sensing parameters of the ventilator. Inthat regard, the breath sensor 14 can be configured to interface withany standard breathing circuit used in critical care ventilators andtherefore the pacing system may be independent of the brand and model ofventilator used. The breath sensor 14, by virtue of its location inseries with the breathing circuit, may monitor and/or measure severalventilation parameters and communicate such parameters to thestimulation control unit 8. The breath sensor 14 can be part of afeedback control scheme for regulating the stimulation administered tothe patient. The sensed, calculated or derived ventilation parametersmay include, but are not limited to, airflow (inspired and/or expired),volume, and pressure (airway, esophageal, gastric, and/or somecombination/derivative of the former). In some embodiments, othersensors may aid in the procurement of one or more ventilationparameters. In one embodiment, the breath sensor 14 may monitor flow,volume, or pressure from the breathing circuit between a patient and aventilator. In another embodiment, the breath sensor 14 may communicatedirectly with the ventilator to determine flow, volume, or pressure.

The example parameters may be measured both to and from the ventilator.The breath sensor 14 may be external to the ventilator so that thesystem is independent of ventilator model. However, the diaphragm pacingsystem could also be integrated to use a ventilator's internal sensorsor the signals externally supplied by the ventilator for properoperation so that an additional external breath sensor can be omitted.

The stimulation control unit 8 may function, in part, as a signalgenerator for providing therapy to the diaphragm in response toinformation received from the one or more of the sensors 12, 14 and/orinformation programmed into the system by the clinician. The clinicianor other user may input information into the stimulation control unit 8using one or more input devices 15. Input device 15 may include akeyboard to manually enter information or may include a ventilator orother device in communication with the stimulation control unit 8. Inputinformation, received from a user or another device, may include anyinformation used during or otherwise relevant to the mapping process ordiaphragm pacing. The stimulation control unit 8 may be configured todeliver fully programmable stimulation.

As shown in FIG. 2, the stimulation control unit 8 of the diaphragmpacing system may further include a power source, a pulse generationcircuit, a timer, a signal processing section, and a controller, eachconfigured to execute, via hardware, software, or any other necessarycomponents, the various functions and processes described herein. Eachof the diaphragm pacing system components shown in FIG. 2 may beelectrically coupled or otherwise in communication with the variousother components. In one embodiment, the controller may be a distributedcontrol system.

Once the catheter is fully inserted in the desired blood vessel(s) (FIG.1), the process of mapping the electrodes can be initialized. Referringto FIG. 3, selective stimulation of the distal set of electrodes may beused to locate the right phrenic nerve, and selective stimulation of theproximal set of electrodes may be used to locate the left phrenic nerve.

Electrode Configuration/Orientation Relative to Nerve

In addition to proximity of electrodes to a nerve, electrodeconfiguration relative to a nerve is a factor that may reduce the amountof electrical current required to stimulate nerve axons. In theory andin practice, nerve axons require lower activation currents when theelectrodes and the direction of current flow are parallel to the nerve(such as shown in FIGS. 4A and 4B), thus producing a longitudinaltransmembrane depolarization of sufficient magnitude to initiate actionpotentials. Since the direction a nerve courses may not be exactly knownand can vary from one individual to another, various electrodecombinations can be tested to ensure that the optimal electrodes areselected during nerve stimulation. The embodiment of FIG. 3 may includetwo parallel rows of electrodes, from among which pairs can be selectedhaving various orientations relative to the catheter and the nerve.

Stimulation Patterns and Recruitment Curve Development During Mapping

Referring to FIG. 5, recruitment curves or sigmoidals may be used tocharacterize the response of the diaphragm to nerve stimulation. Arecruitment curve may be developed by stimulating a nerve with aspecific electrode combination multiple times (e.g., delivering multipleelectrical pulses 76, such as those shown in FIGS. 7-9), measuring thediaphragm's response, and preparing a line of best fit to develop amodel of the diaphragm's response. Thus, recruitment curves may beunique to each stimulation site and electrode combination.

FIG. 5 depicts an example of a recruitment curve 16 that may includefive elements or portions. The first element of the curve is termed ZeroRecruitment, and may correspond to stimulation eliciting no responsefrom the muscle (e.g., the diaphragm). In one embodiment of the ZeroRecruitment portion, two or three electrical pulses 76 (see FIG. 7) maybe delivered to the nerve, which may minimize the time required and thestimulation delivered during this phase. The Zero Recruitment portionmay help a user identify the Activation Threshold, which is when themuscle begins to respond to nerve stimulation. This second portion, theActivation Threshold, may represent a charge level that has a certainchance (e.g., 50%) of causing a threshold activation or contraction ofthe muscle. The Activation Threshold may be defined at any percentageand can be lower or higher than 50%. The third portion, ProportionalRecruitment, is a part of the recruitment curve 16 that describes therelationship between charge level and recruitment between the ActivationThreshold and the Maximal Recruitment level. The ProportionalRecruitment section of the recruitment curve may be used to generatestimulation parameters for use during therapy. The fourth portion,Maximal Recruitment, is the charge level at which the highest possiblemuscle response is generated. The Maximal Recruitment point demarks theend of the Proportional Recruitment section of the recruitment curve.The last portion, termed as Supramaximal Recruitment, is any recruitmentat charges larger than the Maximal Recruitment charge. The slope of thisregion may be less than the Proportional Recruitment region.

One aspect of this disclosure involves the automated,feedback-controlled, generation of a recruitment curve as depicted inFIG. 5, FIG. 10A, and FIG. 10B. As will be described in greater detailbelow, the stimulation control unit 8 may deliver a ramp of stimulationpulses of increasing intensity while monitoring the response of thebody, which may reduce the time required and stimulation deliveredduring the recruitment curve generation process. The ramp of stimulationand quantification of stimulation pulses can be achieved with a singledata point per charge delivered (FIG. 10A), or multiple data points percharge delivered (FIG. 10B).

The automated generation of a recruitment curve may entail thestimulation control unit 8 delivering a ramp of stimulation (a pluralityof electrical pulses 76) based on the physiological response elicited byprior pulses within the ramp of stimulation. In the event thatstimulation and response parameters are not within a configurable rangeor threshold, the control system may halt stimulation and adjuststimulation parameters appropriately. A new ramp of stimulation may thenbe delivered for sigmoidal acquisition at the reconfigured charge. Acomplete recruitment curve may then be generated, without deliveringunnecessary stimulation that would not contribute towards the generationof a satisfactory recruitment curve, as defined by the configurablethresholds. One embodiment may feature a threshold defining theappropriate pulse width range for the activation threshold; ifactivation is not detected within the configured pulse width zone thesystem may halt stimulation and increase or decrease the pulse currentbefore commencing stimulation (see FIGS. 9 and 14C). Other embodimentsmay feature a threshold defining the appropriate current range for theactivation threshold while keeping pulse width constant; if activationis not detected within the configured current zone, the system may haltstimulation and increase or decrease the pulse width before commencingstimulation. Other embodiments can use a combination of parameters toreconfigure charge delivered and may feature configurable zones forparameters including, but not limited to: zero recruitment, proportionalrecruitment, and supramaximal recruitment, as depicted in FIG. 5.

One aspect of the disclosure provides a method for mapping the bestelectrodes for recruiting the phrenic nerves for diaphragm pacing insynchrony with Mechanical Ventilation, without having to discontinueMechanical Ventilation during the mapping process. The method may use amulti-electrode catheter and an automated feedback-control algorithmthat intelligently selects a subsection of electrodes and may minimizethe time required and stimulation delivered as part of the mappingprocess. As described further in connection with FIG. 13, electrodecombinations may be selected for evaluation based on the physiologicalresponse (e.g., the diaphragm response) to prior stimulation. Thephysiological response to stimulation may be quantified by monitoringthe resultant change in the airway pressure, airway flow,Electromyography, chest wall acceleration, or any other signal resultingfrom or correlated with contraction of the diaphragm. In the embodimentof FIG. 8, for example, stimulation may be delivered during theend-expiration (quiet) phase (see FIG. 6) of the patient's breathingcycle, and as such does not interrupt regular Mechanical Ventilation.

FIG. 6 illustrates exemplary airway pressure and airway flow curvesduring inspiration and expiration phases of a breath. A patient mayexhibit such pressure and flow curves while intubated and being assistedby a ventilator. Electrical pulses 76 shown in FIGS. 7-9 may bedelivered to a patient by a diaphragm pacing system, for example, duringend-expiration phases 72 of one or more breaths, during which backgroundflow and pressure values remain relatively constant.

FIGS. 7-9 illustrate exemplary nerve stimulation patterns that may beused to test electrode combinations, which may include development ofall or a portion of a recruitment curve for each electrode combination.Electrode combinations may be tested to locate optimal electrodes forthe desired result, such as phrenic nerve stimulation to pace thediaphragm. The nerve stimulation patterns illustrated in FIGS. 7-9 maybe implemented during any of the various stages of the algorithmsdescribed herein, such as during the testing of electrode combinationsdescribed in connection with FIGS. 13-14C. For some electrodecombinations, the stimulation patterns may be implemented to developfull recruitment curves, such as those shown in FIGS. 5, 10A, and 10B.

FIGS. 7-9 are generalized to show electrical pulses 76 delivered over aperiod of time (x-axis) and each having a certain stimulation charge(y-axis). However, the stimulation charge of each pulse 76 may be variedas a function of current amplitude, pulse width (the length of timecurrent is applied), voltage, or a combination of these parameters. Forexample, referring back to FIG. 5, to achieve the increase in chargeshown along the x-axis, successive electrical pulses 76 may be appliedfor different amounts of time while the current amplitude may be heldconstant. The pulse widths of individual pulses may therefore increasealong the x-axis of FIG. 5. Alternatively, to achieve the increase incharge shown along the x-axis, different current amplitudes may beapplied during successive pulses 76 while the pulse width may be heldconstant. Similarly, voltage may be increased or decreased to increaseor decrease charge. Accordingly, the diaphragm pacing systems andmethods described herein may vary pulse width, current amplitude, orvoltage, or a combination, to achieve varying charge levels.

As shown in FIG. 7, electrical pulses 76 may be delivered in a varietyof patterns. In one embodiment, the diaphragm pacing system may includeat least three stimulation modes: Stim. Mode 1, Stim. Mode 2, and Stim.Mode 3. In a first pattern, referred to as Stim. Mode 1, successivepulses 76 may be delivered during a single end-expiration phase 72. Inone embodiment, each pulse 76 of Stim. Mode 1 may increase in chargerelative to the previous pulse 76. As described above, the increase incharge may be due to a larger pulse width, larger current, largervoltage, or a combination of changes among these parameters. Sixelectrical pulses may be delivered during each end-expiration phase 72.However, in other embodiments, less than or more than six electricalpulses may be delivered during an end-expiration phase 72, and in oneembodiment, three electrical pulses may be delivered during anend-expiration phase 72. The diaphragm response to the pulses 76 ofStim. Mode 1 may allow for development of a recruitment curve for thespecific electrode combination. For example, the pulses 76 of Stim. Mode1 may allow the system to determine the activation threshold and themaximal recruitment level of a nerve when stimulated with the testedelectrode combination.

FIG. 7 further illustrates a second stimulation pattern, referred to asStim. Mode 2. In Stim. Mode 2, similar to Stim. Mode 1, electricalpulses 76 may be delivered during end-expiration phases 72. However, inStim. Mode 2, successive electrical pulses 76 may have charge valuesthat are closer together than the charge values of successive pulses ofStim. Mode 1. Having successive pulses 76 with more closely spacedcharge values may allow for a more accurate determination of therecruitment curve corresponding to the tested electrode combination. Forexample, relative to the pulses shown in Stim. Mode 1 of FIG. 7, thepulses shown in Stim. Mode 2 of FIG. 7 may allow more accuratedeterminations of the activation threshold and the maximal recruitmentlevel.

A third stimulation pattern is shown as Stim. Mode 3 of FIG. 7. In thisexample, the pulses 76 in a single end-expiration phase 72 may each havethe same charge value, although the charge value of pulses 76 indifferent end-expiration phases 72 may be different. For example, thecharge value of pulses 76 in a later end-expiration phase may be greaterthan the charge value of pulses 76 in an earlier end expiration phase.Applying multiple pulses 76 having the same charge during a singleend-expiration phase 72 may allow the diaphragm response to thatelectrode combination and charge to be measured multiple times. Thesystem may take an average or use algorithms to eliminate abnormalresponses, allowing for a more accurate determination of the diaphragmresponse to the specific electrode combination and charge.

The number of pulses delivered during an end-expiratory phase 72, in anyStim. Mode, may be based at least in part on one or more of thefollowing factors: a) the duration of the end-expiratory phase, b) themaximum rate at which the diaphragm pacing system can stimulate, and c)the duration of the diaphragm response (e.g., the change in pressure,air flow, volume, chest acceleration, etc., caused by each pulse 76).The optimal number of pulses 76 delivered during an end-expiratory phase(the optimal rate of stimulation), may be determined by considering oneor more of these factors. As just one illustrative example, stimulationpulses 76 may be delivered at a rate of 4 Hz to allow 250 ms betweenpulses 76, which may be slightly longer than the time it takes for thepressure and air flow waves caused by the pulse 76 and its resultingdiaphragm response to peak and fade away, without overlapping with thenext diaphragm response. However, the frequency of pulse delivery can behigher or lower than 4 Hz and may be varied in accordance with numerousconsiderations and testing conditions. Optimizing the rate ofstimulation during mapping may minimize the overall time required toselect the optimal electrodes for nerve stimulation by using the highestpossible frequency that will still allow for accurate diaphragm responsemeasurements.

FIG. 8 illustrates the exemplary stimulation patterns of FIG. 7 with agraph depicting flow during inspiration and expiration phases. In oneembodiment, the flow shown in FIG. 8 is of a patient receiving breathingassistance from a ventilator. As can be seen in FIG. 8, the pulses 76 ofthe various stimulation modes may be delivered during end-expirationphases 72, when background flow is relatively constant (and close tozero).

FIG. 9A illustrates exemplary flow, stimulation charge, diaphragmresponse, pulse width, and current level during four breaths of apatient. During these four breaths, the patient may be receivingbreathing assistance from a ventilator, and testing of electrodecombinations may occur during the end-expiration phases 72(individually, 72 a, 72 b, 72 c, and 72 d) of the ventilator-assistedbreaths. Flow is illustrated at the top of FIG. 9A. The stimulationcharge of electrical pulses 76 is illustrated just below the flowsignal. The electrical pulses 76 of the diaphragm pacing system mayaffect flow during the end-expiration phases. The diaphragm response tothe electrical pulses 76 is shown below the stimulation charge portionof FIG. 9A. The diaphragm response may be measured as a change in flow,pressure, or other parameter in response to the electrical pulses 76.The pulse width of each electrical pulse 76, which is the length of timeeach pulse 76 is applied, is also shown in FIG. 9A. Finally, at thebottom of FIG. 9A, the current level of each pulse width is illustrated.As can be seen by comparing the stimulation charge, pulse width, andcurrent level graphs of this example, the stimulation charge may bevaried during a single end-expiration phase by modifying the pulsewidth, while current during the same end-expiration phase may remainconstant.

The diaphragm response may aid the pacing system in modifying theelectrical pulses 76 to extract more accurate information about theactivation threshold and maximal recruitment level of the nerve whenstimulated with the tested electrode combination. For example, referringto end-expiration phase 72 a in FIG. 9A, the diaphragm response is lowand relatively steady in response to the first four pulses 76 and thenincreases in response to the fifth pulse 76. Accordingly, the activationthreshold of the nerve may be somewhere between the charge levels of thefourth and fifth pulses 76 of phase 72 a.

To determine a more narrow range for the activation threshold, thepulses 76 delivered during the second end-expiration phase 72 b may allfall within a more narrow range than the range encompassing the chargesof phase 72 a. Similarly, the pulses 76 delivered during the thirdend-expiration phase 72 c may all fall within a more narrow range ofcharges. For example, each pulse 76 delivered during phase 72 b may havea charge between the charges of the third and fifth pulses deliveredduring phase 72 a. Each pulse 76 delivered during phase 72 c may have acharge higher than the charge of the fifth pulse of phase 72 a, with thecharge difference between consecutive pulses 76 being similar to thecharge difference between consecutive pulses 76 of phase 72 b. In thismanner, the system may determine a more accurate estimate of theactivation threshold AT, which may be, for example, the stimulationcharge of the third pulse of phase 72 b (corresponding to an increase inthe diaphragm response during phase 72 b).

During phase 72 c, the diaphragm response in this example increasesproportionally in response to increases in stimulation charge.Accordingly, these charges may fall within the proportional recruitmentsection of a recruitment curve similar to that of FIG. 5. Finally, theelectrical pulses 76 delivered during the fourth end-expiration phase 72d may be used to determine the maximal recruitment level andsupramaximal recruitment portion of the recruitment curve. As can beseen in the diaphragm response portion corresponding to phase 72 d, thediaphragm response saturates and remains steady and high during phase 72d, even though the stimulation charge of each pulse 76 is increasing.

FIG. 9B illustrates exemplary flow, pressure, EMG, and accelerationmeasurements, as determined by one or more sensors 12, 14, in responseto electrical pulses 76. Flow, pressure, EMG activity, and acceleration(e.g., of the chest wall) may be indicative of the diaphragm's responseto electrical pulses 76. As can be seen in FIG. 9B, pressure may drop inresponse to stimulation charges above the activation threshold becausethe diaphragm responds by contracting, which results in expansion of thelungs. EMG activity may increase because the diaphragm muscle has beenelectrically stimulated. Acceleration of the chest wall or other portionof the patient may increase when pulses 76 are above the activationthreshold and the diaphragm is stimulated, expanding the lungs and thechest.

In one embodiment, the diaphragm pacing system is a constant-currentsystem that may deliver pulses 76 having pulse widths within a definedrange. In one example, the defined range for pulse widths is 10-300 μs.In various embodiments, the current may be between 0.1 mA and 10 mA,0.25 mA and 5 mA, or 0.5 mA and 2 mA, and in one example is 1 mA. It maytherefore be useful if the pulse width of a pulse 76 at or near theactivation threshold PW(AT) is within a specific range R, such as therange R shown in hatching in FIG. 9A. Range R may be a portion, such asthe first 20%, of the full pulse width range. In one embodiment, range Ris 10-68 μs. The diaphragm pacing system may therefore modify thecurrent level of pulses 76, as shown between end-expiration phases 72 aand 72 b, to achieve an activation threshold pulse width PW(AT) withinrange R.

FIGS. 10A and 10B illustrate exemplary recruitment curves that may bedeveloped based on the electrode combination testing of FIG. 9A.Referring to FIG. 10A, at shorter pulse widths (e.g., the first twopulses delivered during end-expiration phase 72 b of FIG. 9A), thediaphragm response may be zero or close to zero. This portioncorresponds to the zero recruitment portion of the recruitment curve. Aspulse width increases (e.g., all pulses delivered during end-expirationphase 72 c of FIG. 9A), the diaphragm response may increase generallyproportionally. This section of the curve corresponds to theproportional recruitment section of the curve. Finally, when pulse widthis above a certain level (e.g., all pulses delivered duringend-expiration phase 72 d of FIG. 9A), the diaphragm response maysaturate at its maximum capacity and no longer increase, correspondingto the supramaximal recruitment portion of the recruitment curve. A lineof best fit may be calculated using the data points corresponding to thepulse width of pulses 76 (x-axis) and their resulting diaphragmresponses (y-axis).

To develop the recruitment curve of FIG. 10B, testing of a particularelectrode combination may be carried out multiple times and the datapoints corresponding to tested pulse widths and their elicited diaphragmresponses may be averaged. For example, the process of FIG. 9A, whichtakes place during four breaths, may be repeated one or more timesduring other sets of breaths. The data points may then be averaged, anda line of best fit may be calculated using the averages.

Mapping Process Exemplary Embodiment

FIGS. 11-14C will be referenced to describe an exemplary embodiment of aprocess of testing multiple electrode combinations to determine theoptimal electrode combinations for nerve stimulation. For each testedelectrode combination, electrical pulses 76 may be delivered to a nerveas described above, and the diaphragm pacing system may be capable ofdeveloping a recruitment curve that corresponds to that specificelectrode combination and its effect on the target nerve.

Embodiments of the present disclosure provide systems capable of rapidlyand automatically optimizing the delivery of stimulation via anymulti-electrode pacing catheter such as, for example, the catheterdescribed in U.S. Provisional Application No. 61/907,993 filed Nov. 22,2013, titled “Apparatus for Assisted Breathing by Transvascular NerveStimulation and Related Methods,” and U.S. application Ser. No.14/550,485, filed Nov. 21, 2014, titled “Apparatus and Methods forAssisted Breathing by Transvascular Nerve Stimulation,” the disclosuresof which are incorporated herein. One embodiment provides a method foriteratively evaluating and selecting a subsection of suitablestimulation electrodes in an automated fashion. Stimulation delivery maybe optimized by the selection of an appropriate subsection of electrodessuitable for nerve stimulation without requiring the movement of asatisfactorily-inserted catheter. A catheter may be satisfactorilyinserted if some, or all, of its electrodes are able to produce chargefields that intersect a portion of at least one target nerve.

The iterative evaluation of electrode combinations described inconnection with FIGS. 11-14C may save time during electrode selection byquickly focusing on electrode combinations most likely to provide asatisfactory diaphragm response. First, a subset of electrodecombinations along the length of an elongated body 4, referred to asprimary combinations (see FIG. 11), may be tested to determine thegeneral location of a nerve relative to the elongated body 4. It may notbe necessary to test all possible electrode combinations to determinethe general location of the nerve. Then, based on the localized subsetof primary electrode combinations in proximity to the nerve, additionalcombinations of electrodes, referred to as secondary electrodecombinations, may be tested (see FIG. 12). Localizing a specific area ofthe elongated body 4 and then determining additional electrodecombinations may prevent having to test numerous permutations ofelectrode combinations along the entire length of the elongated body 4.

The system may rapidly converge upon a suitable electrode combination,and its corresponding stimulation parameters, by analyzing and comparingthe diaphragm's response to stimulation delivered across a range ofelectrode combinations. The system may also take into considerationphysiological parameters such as Heart Rate, ECG, central venouspressure, etc. and discard electrode combinations or stimulationconfigurations that manifest undesirable effects of stimulation,including, but not limited to the stimulation of vagus nerve(s), whichmay be anatomically located close to the targeted zones (FIG. 1), theSinoatrial node, etc. A variety of stimulation patterns can be used forthe purpose of comparing responses, such as the patterns described abovein connection with FIGS. 7-9. A multitude of sensors and signalartifacts can be used to quantify the physiological response to astimulation including, but not limited to: electromyography,accelerometers placed in/on body, central venous pressure, blood oxygensaturation, carbon dioxide concentration, catheter position/depth withinvein, mechanical movement, airway flow, and airway pressure.

In one embodiment, stimulation control unit 8 may perform an iterativeprocess of testing and ranking of electrode combinations to convergeonto a suitable electrode combination. By delivering ramps ofstimulation to increasingly smaller sets of electrode combinations, thebest electrode combination may be identified while reducing the overalltime required and charge delivered to the body during the mappingprocess.

In a first stage, the algorithm may identically stimulate a series ofconfigurable electrode combinations that are expected to be suitablyoriented in relation to the phrenic nerve. FIG. 11 provides an exampleof preconfigured electrode combinations. The physiological response canbe described as the summed-total perturbations in any signal artifactcaused by the entire train of stimulation. Based on the comparativedesirable and undesirable physiological response elicited, the algorithmmay identify a location on the inserted catheter that is likely locatedclose to the nerve. Electrode combinations within this identifiedcatheter area, such as those shown in FIG. 12, are likely to be optimalfor stimulation delivery.

In a second stage, the electrodes within this identified area may bestimulated with a ramp of stimulation and comparatively evaluated basedon the elicited physiological response. The physiological response tostimulation delivery can be quantified by a multitude of signalsincluding, but not limited to, electromyography, accelerometers placedin/on body, central venous pressure, blood oxygen saturation, carbondioxide concentration, catheter position/depth within vein, mechanicalmovement, airway flow, and airway pressure. In one embodiment, theairway pressure may be used to quantify the response of the diaphragm toa round of end-expiration stimulation (e.g., as shown in FIG. 8). Acomparison of the responses elicited by the electrode combinationsduring this stage yields a potential multitude of optimal electrodecombinations for stimulation. This multitude of optimal combinations cansubsequently be configured such that they all, or a subsection, of themare used for stimulation delivery during pacing.

FIG. 13 illustrates a general overview of a process for determiningoptimal electrode combinations for nerve stimulation. In step 1310, afirst plurality of electrode combinations along the length of anelongated body 4, such as a catheter, may be tested for their ability tostimulate a target nerve. As noted above, this process may aid inlocating the section of the catheter that is closest to the targetnerve. FIG. 11 corresponds to step 1310, and the arrows in FIG. 11indicate exemplary primary electrode combinations (shown as pairs) thatmay be tested to determine which portion of the catheter is closest tothe target nerve or nerves. In one embodiment, six proximal electrodecombinations may be tested during step 1310 to determine their effect ona left phrenic nerve (e.g., 6 g/6 h, 6 i/6 j, 6 k/ 6 l, 6 m/6 n, 6 o/6p, and 6 q/6 r). Similarly, six distal electrode combinations may betested during step 1310 to determine their effect on a right phrenicnerve (e.g., 6 a/6 b, 6 b/6 c, 6 c/6 d, 6 d/6 e, and 6 e/6 f). However,different proximal or distal primary electrode combinations mayadditionally or alternatively be tested, and less than six or more thansix combinations may be tested during step 1310. After various electrodecombinations have been tested, the stimulation control unit 8 maydetermine, based on the diaphragm response to stimulation from thetested combinations, which section or sections of the catheter arelocated closest to the target nerve or nerves.

In step 1320, a second plurality of electrode combinations identified instep 1310 may be further tested and ranked to determine theirsuitability for nerve stimulation. The second plurality of electrodecombinations may include a subset of the electrode combinations, withina localized area, as well as additional secondary electrodecombinations. FIG. 12 corresponds to step 1320 and illustrates variouselectrode combinations (shown as pairs) that may be further tested. Inone example, the testing of step 1320 results in identification of oneor more proximal electrode combinations as most suitable for stimulationof the left phrenic nerve and identification of one or more distalelectrode combinations as most suitable for stimulation of the rightphrenic nerve.

In step 1330, the suitable electrode combinations identified in step1320 may be tested further, and a recruitment curve, such as therecruitment curves shown in FIGS. 5, 10, and 11, may be developed foreach of the combinations.

FIGS. 14A-14C illustrate in greater detail the steps of FIG. 13. FIG.14A corresponds to step 1310, FIG. 14B corresponds to step 1320, andFIG. 14C corresponds to step 1330.

In the first stage of the mapping process as shown in FIGS. 14A and 11,the stimulation may be delivered to preconfigured electrode combinationsdistributed on the elongated body 4. In this stage, one goal may be toidentify a localized area of the catheter that is likely locatedanatomically closer to the target nerve. In one embodiment, the initialset of preconfigured electrode combinations does not include allpossible electrode combinations along the length of the catheter.Electrode combinations likely to be close to the target nerve may beidentified by comparing their summed-total response to the entire rampof stimulation without necessarily considering the activation thresholdor recruitment curve involved. Electrode combinations that result in themanifestation of undesirable physiological effects may be eliminatedduring this stage.

FIG. 14A illustrates in detail an algorithm for identifying thesubsection of an elongated body 4 located in close proximity to thetarget nerve. In general, in steps 1410-1440, electrical pulses 76 maybe delivered to electrode combinations, and the diaphragm response toeach of the combinations may be processed. In step 1410, the system mayselect an electrode combination out of a first plurality of electrodecombinations (also referred to herein as primary combinations). Thefirst plurality of electrode combinations may be a preconfigured listprogrammed into the stimulation control unit 8. In one embodiment, thefirst plurality of electrode combinations may be the electrode pairsshown in FIG. 11. In steps 1410-1440, each of the electrode combinationsmay be stimulated one at a time.

In step 1420, a nerve may be electrically stimulated by deliveringcurrent to a first electrode combination of the first plurality ofcombinations. The current may be delivered as an electrical stimulationthat includes one or more pulses 76, such as those shown in FIGS. 7-9,each having a pulse width and a current amplitude. Also in step 1420,the algorithm may monitor a patient's response to the electricalstimulation of the nerve. In one embodiment, one or more sensors 12and/or one or more breath sensors 14 may be used to monitor thepatient's response to stimulation. The sensors 12, 14 may provideinformation on, for example, the diaphragm response of the patient(e.g., by sensing flow, pressure, volume, mechanical movement, or anyother parameters indicative of the diaphragm response), whether theelectrical stimulation is causing undesired effects on other anatomicalfeatures (e.g., by sensing electromyographic activity or heart rate), orany other patient responses disclosed herein as measurable by sensors12, 14.

In step 1430, the algorithm may determine whether all electrodecombinations in the first plurality of electrode combinations have beenstimulated. If all electrode combinations have not been stimulated, thealgorithm may move to the next electrode combination in the firstplurality of electrode combinations (step 1440) and proceed to stimulateand process the patient response to the next electrode combination (step1420). In one embodiment, to save time, step 1420 may be halted for aspecific electrode combination if the system has already found anelectrode combination with a lower activation threshold.

When all of the electrode combinations of the first plurality ofelectrodes have been tested, the system may determine whether two ormore of the first plurality of electrode combinations show thresholdactivation (step 1450). A combination may show threshold activation ifthe delivered electrical stimulation (e.g., a set of three electricalpulses 76) encompasses a range between a charge in which the diaphragmdoes not respond and a charge in which the diaphragm does respond. Theresponse (or lack thereof) of the diaphragm may be measured, asdescribed above, by one or more sensors 12, 14.

If two or more of the combinations do not show threshold activation, thesystem may determine whether any electrode combination showssupramaximal recruitment (step 1460). An electrode combination may showsupramaximal recruitment if delivered electrical pulses of increasingcharge do not cause an increase in diaphragm response. If an electrodecombination shows supramaximal recruitment, the system may reduce thecurrent amplitude by one unit (step 1470). If two or more of thecombinations do not show threshold activation (step 1450), and none ofthe combinations cause supramaximal recruitment (step 1460), the currentmay be increased by one unit (step 1480). If two or more combinationsshow threshold activation (step 1450), the diaphragm responses for eachelectrode combination may be added, and the combinations may be rankedin accordance with their corresponding diaphragm responses (step 1490),as determined by one or more sensors 12, 14.

In step 1500, the system determines whether two superior primaryelectrode combinations emerge. An electrode combination may be superiorrelative to another electrode combination if its total eliciteddiaphragm response is greater than the total elicited diaphragm responseof the other electrode combination. Thus, in step 1500, the system maydetermine whether two electrode combinations elicit a greater diaphragmresponse than the other electrode combinations. As noted elsewhere, thediaphragm response may be measured by or derived from information fromone or more sensors 12, 14. In one embodiment, characteristics of thediaphragm response, such as response duration, response relaxation time,and response half decay time (e.g., of changes in flow, pressure, EMGsignals, or other indicators of diaphragm response), may be used to rankelectrode combinations and determine which combinations elicit greaterdiaphragm responses. If two superior combinations do not emerge,combinations may be removed if they are not eligible to be superiorcombinations (step 1510). Two superior combinations may not emerge if,for example, less than two combinations show activation threshold, orseveral combinations elicit diaphragm responses that are very close toeach other. Electrode combinations may not be eligible, for example, ifthey cause stimulation of the vagus nerves or the Sinoatrial node, orcause any other undesirable effects as determined, for example, by oneor more sensors 12, 14. The remaining combinations then may be rankedwith respect to their corresponding activation thresholds (step 1510).In one embodiment, electrode combinations having lower activationthresholds are ranked more highly than electrode combinations havinghigher activation thresholds. A lower activation threshold may allowminimization of the charge delivered to the body during diaphragmpacing. After removal of unsuitable electrode combinations, the systemmay determine whether two superior combinations have emerged (step1520). If two superior combinations do not emerge, the user may benotified (step 1530) for possible repositioning of the elongated body 4.

Alternatively, if two superior combinations do emerge, the currentamplitude may be adjusted such that the approximate activation thresholdmay be achieved by a pulse 76 having a pulse width within the lowest 20%of the pulse width range. In other embodiments, the pulse 76 may have apulse width within another segment of the pulse width range. Thisadjustment may allow systems with constraints on pulse width toimplement testing and development of the full recruitment curve for theparticular electrode combination and nerve.

Finally, the algorithm of FIG. 14A may result in determination of a listof: a) superior primary electrode combinations, and b) correspondingsecondary combinations (step 1550). The primary electrode combinationsmay be a subset of the first plurality of electrode combinations thatwere found, through the algorithm of 14A, to elicit a suitable diaphragmresponse and to be eligible to be a superior combination. A suitablediaphragm response, which may be higher than the diaphragm response ofother electrode combinations, may be an indicator of proximity to thenerve. The corresponding secondary combinations may be determined by thesystem based on the electrodes within the superior primary electrodecombination subset.

For example, referring to FIG. 12, electrode pairs 6 k/6 l and 6 m/6 nare exemplary superior primary electrode combinations, and the remainingpairs, indicated by arrows, are the corresponding secondary combinationsformed based on the superior primary combinations. Other primaryelectrode pairs that are not superior primary combinations, such as 6i/6 j, may be included in the set of secondary combinations because oftheir proximity to the superior primary combinations. For example, ifsuperior primary combination 6 k/6 l is ranked the highest, adjacentelectrodes 6 i/6 j may be included in the set of secondary combinationsfor further testing, even though 6 i/6 j was tested previously as aprimary combination. When tested again, different stimulation parametersmay be used based on the diaphragm responses obtained during testing ofthe primary combinations. The superior primary and correspondingsecondary combinations (step 1550) may together be referred to as asecond plurality of electrode combinations. Developing the secondplurality of electrode combinations from the localized subset of thefirst plurality of electrode combinations may prevent having to test agreater variety of combinations, such as those shown in FIG. 12, alongthe length of the catheter.

Accordingly, in one embodiment, the output of step 1550 (FIG. 14A) andstep 1310 (FIG. 13) may be a second plurality of electrode combinations.The second plurality of electrode combinations may include two primaryelectrode combinations (e.g., two combinations that were tested duringthe algorithm of FIG. 14A) and their corresponding secondarycombinations (e.g., various other electrode combinations that may beformed based on the electrodes of the primary combinations). In otherembodiments, the output of step 1550 and 1310 is less than or more thantwo superior primary electrode combinations, such as one, three, five,or more primary electrode combinations, and any number of correspondingsecondary combinations.

The algorithm described in connection with FIGS. 14A-14C may be carriedout by a diaphragm pacing system to select electrodes for stimulating asingle nerve. In one embodiment, the process may be repeated to selectoptimal electrodes for stimulating a second nerve. For example, if thediaphragm pacing system includes an electrode assembly 2 as described inconnection with FIGS. 1 and 3, the process of FIGS. 14A-14C may beimplemented a first time to determine optimal proximal electrodes forstimulation of a left phrenic nerve and a second time to determineoptimal distal electrodes for stimulation of a right phrenic nerve.

In one embodiment, however, if the mapping process is carried out toselect the optimal electrodes for stimulating the left phrenic nerve andthe right phrenic nerve, testing of proximal and distal electrodes maybe done in parallel. In this embodiment, the process of FIGS. 14A-14C iscarried out on both the proximal and distal sets of electrodes, butelectrical stimulation may be delivered to both left and right phrenicnerves during the same end-expiratory phase or phases. Stimulationpulses 76 may alternate between an electrode combination for stimulatingthe left phrenic nerve and an electrode combination for stimulating theright phrenic nerve, allowing testing and accurate monitoring of bothcombinations during a single breath or breaths. In yet anotherembodiment, the left and right phrenic nerves may be testedsimultaneously, with the process of FIGS. 14A-14C carried out on boththe proximal and distal sets of electrodes. Unilaterally placed sensors12, 14, such as accelerometers, may be used to separately monitor theindividual hemi-diaphragm responses to simultaneous pulses 76stimulating each nerve, and in some embodiments, determine the separatecontributions of the left and right phrenic nerve stimulations.

Referring to FIG. 14B, which illustrates step 1320 of FIG. 13, thesecond plurality of electrode combinations determined in step 1550 ofFIG. 14A may be further tested and ranked. The intermediate steps ofFIG. 14B are similar to those of FIG. 14A and therefore are not repeatedhere. However, the output of the algorithm of FIG. 14B (step 1560) maybe a subset of the second plurality of electrode combinations. In oneembodiment, the output of FIG. 14B may be two electrode combinations forstimulation of a nerve, although the output may be a single electrodecombination or more than two electrode combinations. If the output istwo electrode combinations, both combinations may be used to stimulatethe same nerve, as shown in FIGS. 4A and 4B.

Referring to FIG. 14C, which illustrates step 1330 of FIG. 13, thecombinations identified in step 1560 of FIG. 14B may be further tested.In step 1570, electrical pulses 76 (stimulation) may be delivered havingpulse widths within the first 20% of the full pulse width range (the 20%portion may be the range R shown in FIG. 9A), and the diaphragm responsemay be determined by one or more sensors 12, 14. In one embodiment, thediaphragm pacing system may be in Stim. Mode 2 during step 1570,although other modes and stimulation patterns may be used during thisstep. If the threshold activation is not achieved within the targetpulse width range R (step 1580), the current may be reduced or increaseddepending on whether any zero recruitment is observed (steps 1590, 1600,and 1610). If threshold activation within the target pulse width range Ris achieved (step 1580), stimulation may be continued for the full pulsewidth range (step 1620). The system may determine whether allcombinations have been tested (step 1630) and iterate until eachcombination has been tested (step 1640). Finally, the system may extractthe line of best fit for the data points corresponding to one or more ofthe tested electrode combinations and identify the slope and activationthreshold for the tested combinations (step 1650). The line of best fitmay be a recruitment curve, such as those shown in FIGS. 5, 10A, and10B, corresponding to the tested electrode combination and nerve.

In one embodiment, electrode combinations with recruitment curves havinga greater slope along the proportional recruitment section are selectedfor nerve stimulation over electrode combinations with recruitmentcurves having a smaller slope along the proportional recruitmentsection. A greater slope along the proportional recruitment section mayallow testing for maximal recruitment to be completed more quickly. Inaddition, electrode combinations having a more constant slope along theproportional recruitment section may be selected for nerve stimulationover combinations having a more variable slope because a straightproportional recruitment section may simplify the control of nervestimulation.

In one embodiment, the electrode combinations tested in steps 1310 and1320 of FIG. 13 (also see FIGS. 14A and 14B) are stimulated withelectrical pulses 76 having a consistent ramp of stimulation. Rankingsmay be in accordance with the summed-total response to the consistentramp of stimulation. Accordingly, Stim. Mode 1, as shown in FIG. 8, maybe used in these first two stages of mapping. In Stim. Mode 1, eachtrain of stimulation may be constrained to a single end-expirationphase. Once the best electrode combinations have been determined, thesystem may stimulate nerves using those electrode combinations, analyzethe diaphragm response to each combination, and extract a recruitmentcurve corresponding to each combination.

Referring to FIG. 15, another embodiment provides a method formonitoring the performance of pacing delivered using the diaphragmpacing system. Testing during the mapping processes described above (toselect the optimal electrode combinations) may be carried out at a lowerfrequency than the frequency used for later diaphragm pacing with thoseselected electrode combinations. The diaphragm pacing system thereforehas information, obtained during the mapping process, that can be usedto predict the body's response to the actual diaphragm pacing. Themethod of FIG. 15 may autonomously rectify a degradation of performancevia the use of the mapping and recruitment curve generation methodsdescribed herein. The method may include the constant quantification ofthe response of the body to a round of stimulation delivered (steps1700, 1710, and 1720). If the response evoked is not that which isexpected for a stimulation pulse configured based on a previouslyacquired recruitment curve (step 1730), the system may automaticallyhalt stimulation and reexecute the mapping process of FIG. 13 (step1740). In one embodiment, muscle fatigue, muscle strengthening, orcatheter movement may cause the response of the diaphragm during pacingto be inconsistent with the expected response. One embodiment mayinclude a stimulation control unit 8 that triggers the mapping andrecruitment curve generation process at configurable intervals (e.g., atpreset time intervals), or if it detects any anomalies in thephysiological response relative to the expected physiological response.

While principles of the present disclosure are described herein withreference to illustrative embodiments for particular applications, itshould be understood that the disclosure is not limited thereto. Thosehaving ordinary skill in the art and access to the teachings providedherein will recognize additional modifications, applications,embodiments, and substitution of equivalents all fall within the scopeof the embodiments described herein. Accordingly, the invention is notto be considered as limited by the foregoing description.

1-30. (canceled)
 31. A stimulation system comprising: an electrodeassembly including an electrode combination; a sensor configured tomonitor patient responses to electrical stimulation; a stimulationcontrol unit configured to: deliver a plurality of stimulation pulses tothe electrode combination, wherein each stimulation pulse includes acorresponding charge, and the corresponding charges differ among theplurality of stimulation pulses; determine a relationship between thecorresponding charges and respiratory muscle responses resulting fromthe corresponding charges, and between undelivered charges andrespiratory muscle responses expected from the undelivered charges;after determining the relationship, deliver therapeutic stimulation tothe electrode combination; using the relationship, determine an expectedrespiratory muscle response to the therapeutic stimulation; and comparean actual respiratory muscle response to the expected respiratory muscleresponse.
 32. The system of claim 31, wherein respiratory muscleresponse reflects at least one of a change in: airway pressure, airwayflow, electromyography, or chest wall acceleration.
 33. The system ofclaim 31, wherein determining the relationship includes determining anactivation threshold, and the activation threshold is a charge levelthat has a predefined chance of causing a contraction of the respiratorymuscle.
 34. The system of claim 33 wherein determining the relationshipfurther includes determining a charge causing zero recruitment of aphrenic nerve.
 35. The system of claim 34, wherein determining therelationship further includes determining a range of charges that resultin respiratory muscle responses that increase proportionally.
 36. Thesystem of claim 31, further comprising a device providing respiratoryassistance to the patient.
 37. The system of claim 31, wherein thecharge of each stimulation pulse is a function of at least one ofcurrent amplitude, pulse width, or voltage.
 38. The system of claim 31,wherein the electrode assembly is supported by a catheter configured forinsertion in the patient; and the control unit is further configured toidentify a subsection of the catheter in proximity to a phrenic nerve,prior to determining the relationship.
 39. The system of claim 31,wherein the respiratory muscle is a diaphragm.
 40. The system of claim31, wherein determining the relationship includes calculating a line ofbest fit for a set of data points, where each data point of the set ofdata points represents a respiratory muscle response to a correspondingcharge.
 41. The system of claim 31, wherein determining the relationshipincludes calculating a line of best fit for a set of data points, whereeach data point of the set of data points represents an average ofrespiratory muscle responses to corresponding charges.
 42. The system ofclaim 31, wherein the plurality of stimulation pulses is a plurality offirst stimulation pulses, the corresponding charges included in eachfirst stimulation pulse are corresponding first charges, therelationship is a first relationship curve, the respiratory muscleresponses resulting from the corresponding first charges are firstrespiratory muscle responses, and the control unit is further configuredto: determine the actual respiratory muscle response differs from theexpected respiratory muscle response; halt delivery of therapeuticstimulation; deliver a plurality of second stimulation pulses to theelectrode combination, wherein each second stimulation pulse includes acorresponding second charge, and the corresponding second charges differamong the plurality of second stimulation pulses; and determine a secondrelationship between the corresponding second charges and secondrespiratory muscle responses resulting from the corresponding secondcharges.
 43. A stimulation system comprising: an electrode assemblyincluding a plurality of electrodes; a sensor configured to monitorpatient responses to electrical stimulation; a stimulation control unitconfigured to: determine an electrode combination from the plurality ofelectrodes that is suitable for stimulation delivery; deliver aplurality of stimulation pulses to the electrode combination, whereineach stimulation pulse includes a corresponding charge; determine arelationship relating the corresponding charges and respiratory muscleresponses resulting from the corresponding charges; after determiningthe relationship, deliver therapeutic stimulation to the electrodecombination; using the relationship, determine an expected respiratorymuscle response to the therapeutic stimulation; and compare an actualrespiratory muscle response to the expected respiratory muscle response.44. The system of claim 43, wherein the control unit is furtherconfigured to identify a subsection of the catheter in proximity to aphrenic nerve, prior to determining an electrode combination from theplurality of electrodes that is suitable for stimulation delivery. 45.The system of claim 44, wherein determining an electrode combinationfrom the plurality of electrodes that is suitable for stimulationdelivery includes identifying a subset of electrode combinations thatcorrespond to the subsection of the catheter in proximity to the phrenicnerve.
 46. The system of claim 43, wherein determining an electrodecombination from the plurality of electrodes that is suitable forstimulation delivery includes: delivering stimulation to a predeterminedset of electrode combinations; determining a subset of electrodecombinations based on patient responses to stimulation delivered to thepredetermined set of electrode combinations; and ranking the electrodecombinations of the subset of electrode combinations, based on patientresponses to stimulation delivered to each electrode combination of thesubset of electrode combinations.
 47. The system of claim 43, whereinthe therapeutic stimulation is delivered at a rate, and the rate isbased on a duration of at least one respiratory muscle response.
 48. Thesystem of claim 43, wherein the plurality of electrodes is a firstplurality of electrodes, the electrode assembly includes a secondplurality of electrodes, and the electrode assembly is supported on acatheter configured for placement in the patient such that at least oneof the first plurality of electrodes is proximate a right phrenic nerveand at least one of the second plurality of electrodes is proximate aleft phrenic nerve.
 49. The system of claim 48, wherein the electrodecombination is a first electrode combination, the plurality ofstimulation pulses is a plurality of first stimulation pulses, thecorresponding charges included in each first stimulation pulse arecorresponding first charges, the relationship is a first relationship,the respiratory muscle responses resulting from the corresponding firstcharges are first respiratory muscle responses, and the control unit isfurther configured to: determine a second electrode combination from thesecond plurality of electrodes that is suitable for stimulationdelivery; deliver a plurality of second stimulation pulses to the secondelectrode combination, wherein each second stimulation pulse includes acorresponding second charge; and determine a second relationshiprelating the corresponding second charges to second respiratory muscleresponses resulting from the corresponding second charges.
 50. Thesystem of claim 43, wherein respiratory muscle response reflects atleast one of a change in: airway pressure, airway flow,electromyography, or chest wall acceleration; and wherein determiningthe relationship includes calculating a line of best fit for a set ofdata points, where each data point of the set of data points representsa respiratory muscle response to a corresponding charge or an average ofrespiratory muscle responses to corresponding charges.